Estrogen receptor α (ERα) is a hormone receptor and key driver for over 70% of breast cancers that has been studied for decades as a transcription factor. Unexpectedly, we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERα RNA binding function is uncoupled from its activity to bind DNA and critical for breast cancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP) sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustain cancer cell fitness and elicit cellular responses to stress. Mechanistically, ERα controls different steps of RNA metabolism. In particular, we demonstrate that ERα RNA binding mediates alternative splicing of XBP1 and translation of the eIF4G2 and MCL1 mRNAs, which facilitates survival upon stress conditions and sustains tamoxifen resistance of cancer cells. ERα is therefore a multifaceted RNA-binding protein, and this activity transforms our knowledge of post-transcriptional regulation underlying cancer development and drug response.

雌激素受体 α (ERα) 是一种激素受体，也是 70% 以上乳腺癌的关键驱动因素，数十年来一直将其作为转录因子进行研究。出乎意料的是，我们发现 ERα 是一种有效的非经典 RNA 结合蛋白。我们发现 ERα RNA 结合功能与其 DNA 结合活性无关，并且对乳腺癌进展至关重要。采用全基因组交联免疫沉淀 (CLIP) 测序和功能性 CRISPRi 筛选，我们发现 ERα 相关 mRNA 维持癌细胞的适应性并引发细胞对压力的反应。从机制上讲，ERα 控制 RNA 代谢的不同步骤。特别是，我们证明 ERα RNA 结合介导 XBP1 的选择性剪接以及 eIF4G2 和 MCL1 mRNA 的翻译，这有助于在应激条件下生存并维持癌细胞对他莫昔芬的耐药性。因此，ERα 是一种多方面的 RNA 结合蛋白，这种活性改变了我们对癌症发展和药物反应背后的转录后调控的认识。